The Protective Effects of Up-Regulating Prostacyclin Biosynthesis on Neuron Survival in Hippocampus.
The Protective Effects of Up-Regulating Prostacyclin Biosynthesis on Neuron Survival in Hippocampus.
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上调前列环素生物合成对海马神经元存活的保护作用。
DOI：
10.1007/s11481-019-09896-5
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Ruan,Ke-He
中科院分区：
文献类型：
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作者：
Ling,Qing-Lan;Akasaka,Hironari;Chen,Chang;Haile,ColinN;Winoske,Kevin;Ruan,Ke-He
细胞花生四烯酸(AA)是一种普遍存在于细胞膜上的不饱和脂肪酸，通过上游环氧合酶(COX)亚型(COX-1和COX-2)与相应的下游合成酶的三步反应，代谢成不同的前列腺素，如前列腺素(PGI2)和前列腺素E2(PGE2)。虽然这些前列腺素的血管活动有很好的特点，但它们在海马体中的具体作用却鲜为人知。海马体是大脑中记忆的主要区域。在大脑中理解它的主要障碍是模仿每一种前列腺素的生物合成。为了解决这个问题，我们使用了单链杂交酶复合体(SCHECs)，它可以成功地将细胞内的AA代谢产物控制为所需的PGI2或PGE2。我们的体外研究表明，PGI2含量较高和PGE2含量较低的神经元对淀粉样蛋白β诱导的神经毒性具有存活保护和抵抗作用。进一步扩展到体内模型，产生PGI2的转基因小鼠和阿尔茨海默病(AD)小鼠的杂交显示出恢复的长期记忆。这些发现表明，血管前列腺素PGI2和PGE2对海马神经元的保护(由PGI2)或损伤(由PGE2)施加了显著的调节影响，并引起了人们的关注，即阿司匹林在心血管疾病中的广泛使用可能对神经退行性保护产生负面影响。我们的研究旨在通过使用混合酶将前列腺素合成分别重定向到PGE2和PGI2，来了解前列腺素在海马区的串扰。我们的数据表明，在炎症过程中，血管介质PGI2和PGE2在海马神经元保护(由PGI2)或损伤(由PGE2)方面发挥了显著的调节作用。这些发现也引起了人们的担忧，即非类固醇抗炎药在心血管疾病中的广泛使用可能会对神经退行性保护产生负面影响。
Cellular arachidonic acid (AA), an unsaturated fatty acid found ubiquitously in plasma membranes, is metabolized to different prostanoids, such as prostacyclin (PGI2) and prostaglandin E2(PGE2), by the three-step reactions coupling the upstream cyclooxygenase (COX) isoforms (COX-1 and COX-2) with the corresponding individual downstream synthases. While the vascular actions of these prostanoids are well-characterized, their specific roles in the hippocampus, a major brain area for memory, are poorly understood. The major obstacle for its understanding in the brain was to mimic the biosynthesis of each prostanoid. To solve the problem, we utilized Single-Chain Hybrid Enzyme Complexes (SCHECs), which could successfully control cellular AA metabolites to the desired PGI2or PGE2. Our in vitro studies suggested that neurons with higher PGI2content and lower PGE2content exhibited survival protection and resistance to Amyloid-β-induced neurotoxicity. Further extending to an in vivo model, the hybrid of PGI2-producing transgenic mice and Alzheimer’s disease (AD) mice showed restored long-term memory. These findings suggested that the vascular prostanoids, PGI2and PGE2, exerted significant regulatory influences on neuronal protection (by PGI2), or damage (by PGE2) in the hippocampus, and raised a concern that the wide uses of aspirin in cardiovascular diseases may exert negative impacts on neurodegenerative protection.Graphic AbstractOur study intended to understand the crosstalk of prostanoids in the hippocampus, a major brain area impacted in AD, by using hybrid enzymes to redirect the synthesis of prostanoids to PGE2and PGI2, respectively. Our data indicated that during inflammation, the vascular mediators, PGI2and PGE2, exerted significant regulatory influences on neuronal protection (by PGI2), or damage (by PGE2) in the hippocampus. These findings also raised a concern that the widely uses of non-steroidal anti-inflammatory drugs in cardiovascular diseases may exert negative impacts on neurodegenerative protection.